The present invention is concerned with the use of 5HT3 antagonists for accelerating intestinal lavage in combination with a laxative, in particular an osmotic agent. The present invention is also concerned with the use of said 5HT3 antagonists in combination with a laxative for the treatment of constipation.
Intestinal Lavage
Adequate colon preparation before diagnostic, therapeutic or surgical procedures is important because safety and diagnostic accuracy depend on adequate cleansing of the intestines. Magnesium sulfate (MgSO4) or, more recently, polyethylene glycol (PEG)-electrolyte solutions (e.g., KleanPrep(copyright) or GoLytely(copyright)) have been widely used as lavage solution for colon preparation. These solutions, generally well tolerated by patients, are extremely effective in cleansing the colonic mucosa of faeculent debris. However, fairly large volumes (4 liters) and relatively long preparation times (up to 24 hours) are required. Reduction of the volume to be ingested and shortening of the preparation time would highly increase patient acceptance and comfort.
These agents may also be used to help eliminate parasites following appropriate therapy, for instance these can be used after or in combination with anthelmintics. These osmotic agents may also be used to help eliminate toxic material in some cases of poisoning.
5HT3 Antagonists
5HT3 receptors appear to mediate the excitatory actions of 5-HT (serotonin) in the peripheral nervous system. The peripheral 5HT3 receptor plays a pivotal role in the process of emesis induced by cytotoxic chemotherapy and radiotherapy. Peripheral 5HT3 antagonists are also being studied for the treatment of irritable bowel syndrome and visceral pain. Evidence has accumulated showing the presence of 5HT3 receptors in the central nervous system. Central 5HT3 receptors have been implicated in cognition and memory disorders, anxiety and dopamine modulation of the mesolimbic structures. Antagonists of the 5HT3 receptor have been proposed for treating these disorders. In animal models of anxiety, 5HT3 receptor antagonists have been shown to exert anxiolytic properties similar to those of benzodiazepines but without sedative, anticonvulsant and muscle relaxant actions. Ondansetron hydrochloride, launched in 1990 as an antiemetic, is being studied in clinical trials for the treatment of age-related cognition disorders and generalized anxiety. Recent studies have suggested an interrelation between the serotonergic and dopaminergic systems, especially through the 5HT3 receptor. 5HT3 antagonists may thus have potential as therapeutic agents for the treatment of hyperdopaminergic disease states such as schizophrenia, without presenting the side effects liability generally associated with classic neuroleptics. (Joseph R. Prous, xe2x80x9cThe Year""s Drug News, Therapeutic Targets, 1994 Edition=l ) 
5-HT3-receptor antagonists can be identified by the fact that they are active, for example, in antagonising the Von Bezold-Jarisch chemoreflex evoked by serotonin in rats (Pharmacology and Toxicology, 70, Supp II, 17-22 (1992)).
It is known that 5HT3 receptor antagonists slow colonic transit and may even cause mild constipation. (Aliment. Pharmacol. Therap. (1990), 4, 139-144; Digestive Diseases and Sciences, vol 35, 4, 477-480). Hence it was quite surprising to find that 5HT3 antagonists have a synergistic effect with osmotic agents to obtain intestinal lavage, i.e. an induced form of diarrhea which is quite the opposite of constipation.
Interesting 5HT3 antagonists are Azasetron HCl, Granisetron HCl, Ondansetron HCl, Tropisetron, DAT-582, Dolasetron mesylate, Itasetron, N-3389, Pancopride, Ramosetron HCl, RG-12915, (R)-Zacopride, Lurosetron, E-3620, GK-128, KB-6933, KF-20170, and SL-90.0539.
An equally interesting 5HT3 antagonist is (xe2x88x92)-cis-4-amino-5-chloro-2,3-dihydro-N-[1-[3-[(3,4-dihydro-4-oxo-2-pyrimidinyl)amino]propyl]-3-methoxy-4-piperidinyl]-2,2-dimethyl-7-benzofurancarboxamide, which will be referred to hereinafter as xe2x80x9cCOMPOUND Axe2x80x9d, which is described as compound number 1 of WO 94/12494, published Jun. 9, 1994.
Of course the pharmaceutically acceptable acid or base addition salt of the 5HT3 antagonists are also intended to be included in the present invention. The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the 5HT3 antagonists are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise. for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The 5HT3 antagonists containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
Laxatives
Laxatives are drugs that promote defecation. Precise mechanisms of action of many laxatives remain uncertain because of the complex factors that affect colonic function, prominent variations of water and electrolyte transport among experimental species and preparations, and a certain costiveness of research in this area. Three general mechanisms of laxative action can be described. (1) By their hydrophilic or osmotic properties, laxatives may cause retention of fluid in colonic contents, thereby increasing bulk and softness and facilitating transit. (2) Laxatives may act, both directly and indirectly, on the colonic mucosa to decrease net absorption of water and NaCl. (3) Laxatives may increase intestinal motility, causing decreased absorption of salt and water secondary to decreased transit time. Mostly one recognizes three major classes of laxatives, i.e. 1) dietary fiber and bulk-forming laxatives, 2) saline and osmotic laxatives and 3) stimulant laxatives. (see Goodman and Gilman, seventh edition, pp 994 to 1003).
The bulk-forming laxatives include a wide range of natural and semisynthetic polysaccharides and cellular derivatives that are only partially digested. The undigested portions are hydrophilic and swell in the presence of water to form a viscous solution or gel. The increased intraluminal pressure reflexively stimulates peristalsis, diminishes colonic transit time and produces a soft gelatinous stool (xe2x80x9cRemington""s Pharmaceutical Sciencesxe2x80x9d, page 783-786, 1990, Mack Publishing Company, Easton, Pa., 18th edition).
The stimulant laxatives act on the intestinal tract to increase its motor activity. The more commonly employed agents are the anthraquinone laxatives, such as, e.g. cascara sagrada and senna; the diphenylmethane derivatives, such as, e.g. phenolphtalein and bisacodyl; and castor oil (xe2x80x9cRemington""s Pharmaceutical Sciencesxe2x80x9d, page 783-786, 1990, Mack Publishing Company, Easton, Pa., 18th edition).
Saline and osmotic laxatives are the primary class of laxatives envisaged in this invention.
Saline and osmotic laxatives include various magnesium salts; the sulfate, phosphate, and tartrate salts of sodium and potassium; the dissacharide lactulose; glycerin; and sorbitol. They are poorly and slowly absorbed and act by their osmotic properties in the luminal fluid.
Two examples of these osmotic agents which are commercially available for intestinal cleansing are KleanPrep(copyright) and GoLytely(copyright).